B cell depletion dramatically affects clinical symptoms in RA patients, this observation suggests that B cells are involved in the pathogenesis of the disease. In addition to the "primary" function (autoantibody production) of B cells these cells express costimulatory molecules and cytokines, which may have profound effects on the initiation and/or chronic progression of disease. However, very little is known about how these other functions of B cells are involved in RA. Our animal model, proteoglycan (PG)-induced arthritis (PGIA), has many similarities to RA and so has the potential to provide important information on the mechanism of human disease. PGIA is critically dependent on PG-specific T cell activation and autoantibody production, consequently, if either of these components are missing arthritis does not develop. The overall goal of this proposal is to understand the mechanisms by which B cells contribute to PGIA. Our strategy in aim 1 is to more closely link PGIA to RA by showing that depletion of B cells in acutely arthritic mice suppresses arthritis. The immunological parameters that correlate B cell depletion with reduction in arthritis will be assessed. Our hypothesis is that T cell activation will be reduced in B cell depleted mice. Furthermore, we hypothesize that costimulatory molecules and cytokines expressed by B cells play a key role in maintaining T cell activation. Hence, in aim 2 and aim 3 we will begin to dissect the mechanisms by which B cells contribute to arthritis. Because cells other than B cells express costimulatory molecules and cytokines we need a strategy to separately examine the role of B cells from other antigen-presenting populations. Our approach is to generate mice with either selective deletion, or reciprocally, selective expression of costimulatory molecules (CD80/86, B7RP-1, and PD-L1) or cytokines (IFN-gamma and IL-10) in B cells and not other cell populations. Our overall hypothesis is that B cells are able to control the development of arthritis through stimulatory and inhibitory interactions that principally affect T cell activation. This is an important area of investigation, which is expected to shed new light on the mechanisms of B cell function in RA, and more generally in autoimmune disease, and thereby provide novel potential targets for the development of therapeutic strategies to selectively block or enhance immune responses.